The principal investigator for this proposal, Dr. Mei Sun, is an Instructor at the West Roxbury VA Hospital / Harvard Medical School. The work outlined in this proposal will serve to further the mentored transition of Dr. Sun into gene therapy of aging related neurodegenerative diseases, and from a research associate to an independent academic investigator applying for RO1 level funding. The mentor in this proposal, Dr. Geller is an independent scientist with extensive published experience on neurobiology and gene therapy. A number of scientists and neurologists including Drs. Geller, Goldstein, Maher, Holmes, Cook, and Shiromani will serve as Dr. Sun's advisors. These scientists will provide her both intellectual and technical advice in their fields of expertise, and will oversee Dr. Sun's progress throughout the grant period. In this proposal, we will investigate an improved gene therapy for Parkinson's Disease. Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects the aging brain, and the symptoms of PD are principally due to degeneration of nigrostriatal neurons. Current treatments center around restoring striatal dopamine levels and are effective initially. But these treatments gradually lose efficacy, and they do not alter the progression of the Disease. Thus, improved treatments for PD should first, restore the function of the nigrostriatal system, and second, alter progression of the Disease by protecting the remaining nigrostriatal neurons. Our laboratory has previously shown that expression of tyrosine hydroxylase (TH) in striatal cells supports long-term biochemical and behavioral correction of a rat model of PD. I have recently shown that co-expression of TH and aromatic amino acid decarboxylase (AADC) supports both biochemical and behavioral correction of the rat model of PD. Many investigators have shown that glial cell line-derived neurotrophic factor (GDNF) can protect nigrostrital neurons in rodent and primate medols of PD. We now propose to systematically develop an improved gene therapy for PD by two complementary treatment strategies. Gene transfer is performed using a helper virus-free Herpes Simplex Virus vector system pioneered in this Laboratory. The first specific aim will improve biochemical and behavioral correction by investigating the preferred combination of genes (TH, GTP cyclohyrolase, AADC, a vesicular monoamine transporter) to support production and release of dopamine. The second specific aim will combine the 'preferred combination of genes to restore striatal dopamine levels with GDNF to protect nigrostriatal neurons. The long-term goal is to develop human gene therapy for PD.